The etiology of rheumatoid arthritis (RA), a chronic, destructive, debilitating arthritis that disproportionately affects women, remains incompletely understood. It is considered to be a multifactorial disease, resulting from the interaction of both genetic and environmental factors. Epidemiologic research has produced convincing data for strong environmental risk factors, including cigarette smoking, exogenous hormone use and female reproductive factors. Recently, advances in human genetics have identified 22 risk alleles associated with RA. Alcohol use, as an important lifestyle factor, has been associated with reduced risk of RA based on previous case-control studies. However, most case-control studies which ascertained alcohol exposure retrospectively were limited by the recall bias. The only prospective cohort study on alcohol and RA was limited by small number of cases, and used a one time self-reported alcohol measure that may induce misclassification bias of exposure status. Thus well-controlled prospective cohort studies with larger sample size and more accurate alcohol measures are needed. The Nurses'Health Studies (NHS) are among the largest and longest running investigations of factors that influence women's health in the World. Started in 1976 and expanded in 1989, the information provided by the 238,000 dedicated nurse-participants has provided the unique opportunity to study rare diseases such as RA. We propose the following specific aims based on existing NHS data: 1) To investigate the association between alcohol consumption and the development of RA in women after controlling for age, race, cigarette smoking, reproductive factors and exogenous hormone use using entire NHS cohorts. All RA incident cases were confirmed by 2 board-certified rheumatologists according to American College of Rheumatology classification criteria. Alcohol consumption was assessed repeatedly within a semi-quantitative food frequency questionnaire started from 1980 in NHS 1 and 1989 in NHS II to the last cycle of the questionnaire for non-cases and before RA onset for cases. We will use cumulative average alcohol consumption across repeated measures instead of one-time measure to best represent long-term alcohol consumption. 2) To investigate interactions between 22 identified genetic risk alleles for RA and alcohol consumption using a matched case-control subsample with genotyping (500 incident RA cases, 500 matched controls) nested in NHS cohorts. These innovative studies will advance understanding of RA etiology and furnish additional information for RA prevention strategies, and provide potential public health implications how a modifiable lifestyle factor may influence the risk of developing RA. PUBLIC HEALTH RELEVANCE: Alcohol use as an important lifestyle factor may be associated with decreased risk of RA. However, definitive data supporting this association from well-controlled prospective studies are lacking. Findings from this large cohort study will clarify the possible protective effect of alcohol use on risk of RA in women and furnish additional information for RA prevention strategies.